THE  CAUSE  OF  GASTRIC 
ULCER 

, UNIVrRSJT^  or  If  r l \ 

N0V  cy  .. 


w. 

E. 

BURGE, 

AND 

Ph.D. 

E. 

L. 

BURGE, 

A.M. 

URBANA,  ILL. 


a , 


Reprinted  from  The  Journal  of  the  American  Medical  Association 
April  1 , 1916 , Fo/.  LXF7,  />/>.  \998-1000 


Copyright,  1916 
American  Medical  Association 
Five  Hundred  and  Thirty-Five  North  Dearborn  Street 
CHICAGO 


THE 


CAUSE  OF  G0&m€/  '•UEi(®  ^*W 


W.  E.  BURGE,  PhD. 


AND 


E.  L.  BURGE,  A.M. 


URBANA,  ILL. 


A great  many  theories  have  been  advanced  concern- 
ing the  cause  of  gastric  ulcer.  The  main  feature  of 
most  of  these  theories  is  that  there  is  a decreased 
resistance  of  limited  areas  of  the  gastric  wall  followed 
by  the  digestion  of  these  areas  by  the  unrestricted 
action  of  the  pepsin.  The  investigation  reported  in  this 
paper  is  concerned  with  the  cause  of  this  diminished 
resistance.  It  has  been  recognized  for  a long  time  that 
the  resistance  to  the  action  of  the  digestive  juices  of 
limited  portions  of  the  mucosa  of  the  stomach  is 
decreased  by  cutting  off  the  blood  supply  to  these  por- 
tions as,  for  example,  by  a clot  in  a small  -blood  vessel 
(thrombosis)  or  by  the  ligation  of  the  vessel.  Under 
such  conditions  the  area  is  digested  by  the  pepsin  with 
the  formation  of  an  ulcer.  The  decreased  resistance  of 
the  areas  rendered  anemic  by  cutting  off  the  blood  sup- 
ply has  usually  been  attributed  to  the  deprivation  of 
the  areas  of  nutrition.  The  frequency  of  the  occur- 
rence of  gastric  ulcer  among  anemic  persons  has  led 
many  to  consider  anemia  a predisposing  factor  in  the 
production  of  ulcer.  Lesions  produced  in  the  mucosa 
of  normal  healthy  animals  heal,  as  a rule,  with  more  or 
less  ease.  If,  however,  the  animal  is  rendered  anemic 
by  bleeding  or  by  the  introduction  of  some  hemolytic 
agent,  lesions  in  the  gastric  mucosa  heal  very  tardily. 
When  the  blood  supply  to  a portion  of  the  mucosa  is 
cut  off,  among  other  things,  the  part  is  deprived  of 
oxygen,  and  for  that  reason  the  oxidative  processes  are 
decreased. 

Araki* 1  showed  that  the  oxidative  processes  are 
decreased  in  rabbits  rendered  anemic  by  bleeding.  In 


* From  the  Physiological  Laboratory  of  the  University  of  Illinois. 

1.  Araki:  Ztschr.  f.  physiol.  Chem.,  1894,  xix,  424. 


2 


phosphorus  poisoning  the  oxidative  processes  of  the 
body  are  decreased,2  and  it  has  been  observed  that 
under  these  conditions  the  tendency  of  the  tissues  to 
undergo  autolysis  is  increased.3  In  diseases  of  the  cir- 
culatory and  respiratory  systems,  where  the  amount  of 
oxygen  is  decreased  and  hence  the  oxidative  processes 
are  decreased,  there  is  a great  tendency  of  all  the 
tissues  to  undergo  self-digestion.4  These  facts  would 
seem  to  point  to  some  relation  between  the  oxidative 
processes  of  the  body  and  the  resistance  of  the  tissues 
to  the  digestive  action  of  the  proteolytic  enzymes. 
Burge5  showed  that  pepsin  as  well  as  trypsin  is  easily 
destroyed  by  oxidation.  Lillie6  showed  that  the  cells 
of  the  gastric  mucosa  possess  intense  oxidative  proper- 
ties. 

In  view  of  the  fact  that  pepsin  is  easily  destroyed  by 
oxidation,  that  the  cells  of  the  mucosa  possess  oxi- 
dative properties,  and  that  these  cells  become  easily 
digested  when  these  properties  are  decreased,  the 
hypothesis  is  advanced  that  the  mucosa  is  not  digested 
under  normal  conditions  because  the  pepsin  immedi- 
ately in  contact  with  the  wall  of  the  stomach  is  ren- 
dered inert  by  the  oxidative  processes  of  the  cells. 
This  theory  assumes  that  normally  a balance  exists 
between  the  oxidative  processes  of  the  cells  of  the 
mucosa  and  the  digestive  action  of  the  pepsin  in  the 
stomach.  If  this  balance  is  destroyed,  as  for  example 
by  depriving  a limited  area  of  oxygen  by  cutting  off 
the  blood  supply,  thereby  decreasing  the  oxidative 
processes  of  the  area,  this  area  should  be  digested  by 
the  pepsin  with  the  production  of  ulcer.  That  the 
mucosa  is  digested  with  resulting  ulcer  under  such  a 
condition  has  been  verified  by  many  observers. 

REPORT  OF  EXPERIMENTS 

The  following  experiments  were  devised  to  imitate 
the  protective  mechanism  as  set  forth  in  the  foregoing 
hypothesis : 

2.  Welsch:  Arch,  internat.  de  pharmacod.  et  de  therap.,  1905,  xiv, 
211.  Ries:  Berl.  klin.  Wchnschr.,  1905,  xlii,  44a,  54. 

3.  Jacoby:  Ztschr.  f.  physiol.  Chem.,  1900,  xxx,  174. 

4.  Schlesinger:  Beitr.  z.  chem.  Physiol,  u.  Path.  (Hofmeister’s) , 
1904,  iv,  87. 

5.  Burge:  Am.  Jour.  Physiol.,  1915,  xxxvii,  462. 

6.  Lillie:  Am.  Jour.  Physiol.,  1902,  vii,  413. 


3 


In  Figure  1,  a is  a rubber  cuff  holding  vessels  b and  c in 
position  as  indicated;  d , a piece  of  platinum  mesh  tied  over 
the  end  of  cylinder  b,  and  e a piece  of  gastric  mucosa  of  the 
dog  tied  over  the  platinum  mesh.  Before  the  platinum  mesh 
was  tied  over  the  end  of  the  cylinder,  platinum  black  was 
deposited  on  it  by  means  of  the  direct  electric  current.  To 
15  c.c.  of  gastric  juice  of  the  dog,  15  c.c.  of  hydrogen  peroxid 
were  added,  and  the  resulting  solution  was  made  acid  with 
hydrochloric  acid  to  the  same  extent  as  the  original  gastric 
juice.  This  solution  was  poured  into  cylinder  b , and  the 
whole  preparation  placed  in  a water  bath  at  38  C.  (100.4  F.). 
Immediately  after  the  solution  was  poured  into  the  cylinder, 


Fig.  1.— Diagram  of  apparatus:  a,  rubber  cuff  holding  glass  vessels 
b and  c in  position;  d,  platinum  mesh;  e,  piece  of  gastric  mucosa. 


an  evolution  of  oxygen  gas  was  observed  in  the  region  of  the 
platinum  mesh.  This,  of  course,  was  due  to  the  decomposition 
of  the  hydrogen  peroxid  by  the  platinum  black.  Thus  the 
mucosa  was  exposed  to  the  action  of  the  gastric  juice  in  the 
presence  of  atomic  oxygen.  After  six  hours,  the  piece  of 
mucosa  was  removed  from  the  tube  and  photographed  (Fig. 
2 A).  It  may  be  seen  that  the  central  circular  area  exposed 
to  the  action  of  the  gastric  juice  in  the  presence  of  atomic 
oxygen  had  not  been  digested. 

Another  preparation,  similar  to  the  one  described,  except 
that  no  platinum  black  was  deposited  on  the  platinum  mesh, 
was  made  and  placed  in  the  water  bath  at  38  C.  On  addition 
of  the  gastric  juice  diluted  with  hydrogen  peroxid  no  oxygen 
was  given  off,  there  being  no  platinum  black  on  the  mesh; 
hence  this  piece  of  mucosa  was  exposed  to  the  action  of  the 


4 


gastric  juice  in  the  absence  of  atomic  oxygen.  Figure  2 B is 
a photograph  of  the  piece  of  mucosa  after  the  preparation 
had  been  in  the  bath  for  sixty-five  minutes.  It  may  be  seen 
that  the  central  circular  area  exposed  to  the  action  of  the 
gastric  juice  had  been  completely  digested  with  the  formation 
of  a hole.  In  Figure  2 A the  oxidation  produced  by  the 
atomic  oxygen  liberated  at  the  surface  of  the  dead  mucosa 
protected  it,  while  in  Figure  2 B,  no  such  protection  being 
afforded,  the  exposed  circular  area  was  readily  digested’  with 
the  production  of  what  corresponds  to  gastric  ulcer.  Figure 
2 C is  a perforating  ulcer  of  the  stomach  shown  for  com- 
parison. 

The  following  experiments  were  carried  out  on  uni- 
cellular organisms  t-o  show  that  when  they  are  intro- 


a b c 

Fig.  2. — Pieces  of  gastric  mucosa.  The  central  areas  of  A and  B 
were  exposed  to  the  action  of  gastric  juice,  A in  the  presence  of 
atomic  oxygen,  B,  in  the  absence  of  atomic  oxygen.  C,  perforating 
ulcer  of  the  stomach. 


duced  into  a solution  of  trypsin  they  protect  them‘- 
selves  from  being  digested  by  means  of  their  oxidative 
processes : 

One  hundred  c.c.  of  clear  pancreatic  juice  were  collected 
from  a cannula  in  the  pancreatic  duct  of  a dog  as  the  result 
of  the  repeated  injections  of  secretin  into  the  jugular  vein. 
The  trypsinogen  in  this  juice  was  converted  into  active 
trypsin  by  the  addition  of  5 c.c.  of  enterokinase.  The  result- 
ing trypsin  solution  was  sterilized  by  exposing  it  for  a few 
minutes  to  ultraviolet  radiation.  It  was  then  placed  in  a 
collodion  tube  and  dialyzed  against  5 liters  of  distilled  water 
for  twenty-four  hours  at  10  C.  (50  F.)  to  get  nd  of  most  of 
the  dissolved  salts. 

Five  c.c.  of  the  activated  dialyzed  juice  were  introduced 
into  each  of  two  long  test  tubes.  Five  drops  of  water  con- 


5 


taining  a great  number  of  living  parameciums  were  intro- 
duced into  one  tube  and  another  five  drops  of  water  contain- 
ing dead  parameciums,  killed  by  exposure  to  ultraviolet  radia- 
tion, into  the  other.  Both  tubes  were  placed  in  a water  bath 
at  30  C.  (86  F.).  At  the  end  of  three  hours,  the  parameciums, 
killed  by  exposure  to  ultraviolet  radiation  before  being  intro- 
duced into  the  pancreatic  juice,  were  completely  digested, 
while  those  introduced  alive  were  as  active  as  at  the  begin- 
ning of  the  experiment.  At  the  end  of  seventy-two  hours, 
when  the  experiment  was  discontinued,  these  parameciums 
were  still  alive  and  very  active. 

These  two  experiments  show,  as  has  been  recognized  for  a 
long  time,  that  living  cells  are  very  resistant  to  the  action  of 
proteolytic  enzymes,  while  dead  cells  are  digested  with  more 
or  less  ease. 

The  digestive  strength  of  the  trypsin  and  the  resistance  of 
the  living  parameciums  having  been  determined  by  these 
control  experiments,  an  attempt  was  made  to  lower  the  resis- 
tance of  the  organisms  to  tryptic  activity  by  decreasing  their 
oxidative  processes.  Five  c.c.  of  the  activated  dialyzed  pan- 
creatic juice  were  exposed  to  the  radiation  from  a quartz 
mercury-vapor  burner  for  one  hour  to  destroy  the  trypsin. 
Living  parameciums  were  introduced  into  this  inactive  juice, 
and  hydrogen  gas  was  bubbled  through  it  for  ten  hours  at 
30  C.  The  purpose  of  bubbling  the  hydrogen  gas  through  the 
juice  was  to  deprive  the  parameciums  of  most  of  the  oxygen 
dissolved  in  the  liquid  and  thus  decrease  the  oxidative  proc- 
esses of  the  parameciums.  At  the  end  of  the  ten  hours  the 
organisms  were  alive  and  active.  This  experiment  shows 
that  the  hydrogen  gas  bubbled  through  the  liquid  was  not 
injurious  to  the  parameciums  and  that  there  remained  in  the 
liquid  sufficient  oxygen  for  the  life  processes  of  the  organ- 
isms. 

Five  drops  of  water  containing  parameciums  were  intro- 
duced into  5 c.c.  of  the  activated  dialyzed  pancreatic  juice. 
Hydrogen  gas  was  bubbled  through  this  liquid  as  it  had  been 
through  the  inactive  juice  containing  the  parameciums.  The 
organisms  were  observed  under  the  microscope  at  frequent 
intervals  during  the  experiment.  After  about  two  hours  the 
animals  were  observed  to  move  less  rapidly  than  at  the 
beginning  of  the  experiment.  A little  later  these  slowly  mov- 
ing organisms  became  more  transparent  and  moved  more 
slowly.  As  digestion  proceeded,  the  transparency  of  the 
parameciums  increased,  and  at  the  end  of  the  third  hour  the 
partially  digested  organisms  appeared  as  shadows.  About 
half  an  hour  later  these  parameciums  had  been  completely 
digested  and  had  gone  into  solution.  These  organisms  were 
literally  digested  while  alive  and  killed  by  the  action  of  the 
trypsin  itself  in  the  process  of  digestion. 

The  preceding  experiment  was  repeated,  and  when  the 
animals  • were  partially  digested,  the  bubbling  of  hydrogen 


6 


gas  through  the  liquid  was  discontinued  and  the  bubbling  of 
oxygen  gas  was  substituted.  When  this  was  done,  the 
organisms  that  had  not  been  too  much  digested  were  revived, 
and  lived  on  as  normal  animals. 

These  experiments  show  that  the  resistance  of  these  unicel- 
lular organisms  to  the  digestive  action  of  trypsin  is  greatly 
reduced  when  their  oxidative  processes  are  decreased,  and 
that  their  resistance  returns  when  the  oxidative  processes  are 
restored.  The  results  obtained  on  these  living  unicellular 
organisms  would  appear  to  lend  support  to  the  hypothesis 
advanced- in  explaining  the  resistance  of  the  living  cells  of 
the  gastric  mucosa  to  the  digestive  action  of  pepsin. 

CONCLUSIONS 

The  decreased  resistance  of  a circumscribed  area  of 
the  stomach  to  the  digestive  action  of  gastric  juice  is 
due  to  a decrease  in  the  oxidative  processes  of  the  cells 
of  the  area.  Gastric  ulcer  is  due  to  the  subsequent 
digestion  of  the  area  by  pepsin. 

The  resistance  of  unicellular  organisms  (parame- 
ciums)  to  the  digestive  action  of  the  proteolytic 
enzymes  can  be  increased  or  decreased  by  increasing 
or  decreasing  the  intensity  of  the  oxidative  processes 
of  the  organisms,  the  greater  the  intensity  of  the  oxi- 
dative processes  the  greater  the  resistance,  and  vice 
versa. 


■ 


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